(2R-trans)-N-[2-(1,3,4,6,7,12b-hexahydro-2'-oxospiro[2H-benzofuro[2,3-a]qui nolizine-2,4'-imidazolidin]-3'-yl)ethyl]methanesulfonamide and certain other (2R-trans)hexahydroaroquinolizines which may be named (2R-trans)-N-(2-(1,3,4,6,7,12b-hexahydro-2'-oxosphiro[2H-aro[2,3-a]quinoli zine-2,4'-imidazolidin]-3'yl)ethyl)methanesulfonamide and represented by the formula ##STR1## wherein ##STR2## is an aromatic ring system as hereinafter defined are peripherally selective .alpha..sub.2 -adrenoceptor antagonists. As peripherally selective .alpha..sub.2 -adrenoceptor antagonists, they are adapted to be employed for the treatment of certain pathological disorders, such as hypertension, diabetes, obesity disorders involving platelet aggregation and gastrointestinal motility and the like, without side effects attributable to the effect of the drug on the central nervous system. They have been found to be especially useful in the treatment of diabetes.
In the foregoing formula, ##STR3## is a divalent radical of an aromatic ring system selected from ##STR4## wherein R.sup.1 and R.sup.2 are independently hydrogen, halo, hydroxy, C.sub.1-3 alkoxy, lower alkyl or carboxy, or together are methylenedioxy or C.sub.3-4 alkylene; and
wherein the free bonds of Ar are attached to the quinolizine ring in either configuration of ##STR5##
The compounds of formula (I) are included in those disclosed in copending application Ser. No. 76,495, filed Jul. 27, 1987 now U.S. Pat. No. 4,831,035, May 16, 1989, which is a continuation-in-part application of Ser. No. 901,485, filed Aug. 28, 1986, now abandoned. The application issued into South African Patent 87/6400 on Apr. 27, 1988.
In the present application, the compounds of formula (I) are referred to as (2R-trans)-N-[2-(1,3,4,6,7,12b-hexahydro-2'-oxospiro[2H-aro-[2,3-a]quinoli zine-2,4'-imidazolidin]-3'-yl)ethyl]methanesulfonamide. This is a preferred Chemical Abstracts nomenclature. In the aformentioned copending application and South African patent, the nomenclature employed to designate the compounds represented by formula (I) would be (2R,12bS)-3'-(2-methanesulfonamideoethyl)-spiro-[1,3,4,6,7,12b-hexahydroar o-[2,3-a]quinolizin]-2,4'-imidazolidin-2-one. Thus, one of the compounds in the aforementioned South African patent, in which the "aro" group is "benzofuro" and having the formula: ##STR6## would be named, using the Chemical Abstracts nomenclature, (2R-trans)-N-[2-(1,3,4,6,7,12b-hexahydro-2'-oxospiro[2H-benzofuro[2,3-a]qu inolizine2,4'imidazolidin]-3'-yl)ethyl]methanesulfonamide but would be named in accordance with the nomenclature used in the patent as (2R,12bS)-3'-(2-methanesulfonamidoethyl)-spiro-[1,3,4,6,7,12b-hexahydroben zo[b]furo[2,3-a]quinolizin]-2,4'-imidazolin-2'-one.
In the latter patent may be found described a process for the preparation of the compounds. The preparation requires a number of steps and includes certain steps which are not adaptable to large scale synthesis.
The process described in the foregoing patent may be represented by the following flow diagram: ##STR7##
Thus, in accordance with the foregoing flow diagram, a quinolizin-2-one compound (A) and a 2-aminoethylmethanesulfonamide are caused to react in methanolic tetrahydrofuran, followed by the reaction of the product with diethyl cyanophosphonate to obtain in accordance with Step (a), an intermediate Compound B which after recovery and purification by chromatography is reduced with lithium aluminum hydride according to Step (b) to obtain intermediate Compound C. Compound C, after purification by chromatography, is caused to react with carbonyldiimidazole (Step (c)) to obtain Compound I. The latter is then recovered and purified by chromatography.
The process employing the foregoing sequence of reactions is not suitable for large scale preparation and/or manufacturing. Thus, initially, chromatography which is used in most steps of the published synthesis is not generally appropriate or practical for purification on a large scale. Crystallization is a useful purification method adaptable to large scale preparations; thus where possible, compounds are converted to their salts which generally form crystals readily. Thus, in the foregoing flow diagram, Compound B may be purified on a large scale by forming an acid addition salt such as a bis hydrogen chloride addition salt. However, in order to carry out the next step, the hydrogen chloride addition salt, must be converted back to the free base. Conversion to the free base is accompanied by decomposition and hydrolysis with losses of about 15 percent or even higher. The free base decomposes into an imine of the structure: ##STR8## or its hydrolysis product which is the starting material, Compound A. These by-products give rise in the next reduction step to the following compounds: ##STR9## which are difficult to separate from the desired intermediate Compound C.
Moreover, in Step (b), the lithium aluminum hydride used as reducing agent is undesirable on a large scale because of the hazardous nature of reactions when large amounts of this reducing agent are employed. Other reagents providing less hazardous reaction conditions are ineffective for this reaction. In addition, the isolation of Intermediate C from the reaction mixture after a lithium aluminum hydride reduction is extremely difficult on a large scale because of binding by the amine groups to the aluminum by-products.
Thus, it is desirable to find a more efficient and safe process for proceeding from Compound A to the desired Compound I.